Saireito (TJ-114), a Japanese Traditional Herbal Medicine, Reduces 5-Fluorouracil-Induced Intestinal Mucositis in Mice by Inhibiting Cytokine-Mediated Apoptosis in Intestinal Crypt Cells

Abstract

Clinical chemotherapy frequently causes intestinal mucositis as a side effect, which is accompanied by severe diarrhea. We recently showed that the cytokine-mediated apoptotic pathway might be important for the development of intestinal mucositis induced by 5-fluorouracil (5-FU). Saireito, the traditional Japanese herbal (Kampo) medicine, is widely used to treat diarrhea and various inflammatory diseases in Japan. In the present study, we investigated the effect of saireito on 5-FU-induced intestinal mucositis in mice, especially in relation to apoptosis in the intestinal crypt. Male C57BL/6 mice were given 5-FU (50 mg/kg), i.p. once daily for 6 days. Intestinal mucositis was evaluated histochemically. Saireito (100–1000 mg/kg) was administered p.o. twice daily for 6 days. Repeated 5-FU treatment caused severe intestinal mucositis including morphological damage, which was accompanied by body weight loss and diarrhea. Daily administration of saireito reduced the severity of intestinal mucositis in a dose-dependent manner. Body weight loss and diarrhea during 5-FU treatment were also significantly attenuated by saireito administration. The number of apoptotic and caspase-3-activated cells in the intestinal crypt was increased, and was accompanied by up-regulated tumor necrosis factor (TNF)-α and interleukin (IL)-1β mRNA within 24 h of the first 5-FU injection. However, all of these measures were significantly lower after saireito administration. These results suggest that saireito attenuates 5-FU-induced intestinal mucositis. This action may come from the reduction of apoptosis in the intestinal crypt via suppression of the up-regulation of inflammatory cytokines. Therefore, saireito may be clinically useful for the prevention of intestinal mucositis during cancer chemotherapy.

Effect of the polyphenol composition BP‑C3 on haematological and intestinal indicators of 5‑fluorouracil toxicity in mice

“…Traditional Japanese medicines have been demonstrated to protect intestinal epithelium during 5-FU use (33). Besides their direct antioxidant effect, vegetable and fruit flavonoids are able to increase the activity of detoxifying enzymes (34).…”

Induced overexpression of CD44 associated with resistance to apoptosis on DNA damage response in human head and neck squamous cell carcinoma cells

“…Chinese herbal medicine is a mixture of many herbs following the theory of traditional Chinese medicine (11,12). Among these herbs, the main drugs that contain Scutellaria root are Shosaikoto (Xiao-Chai-Hu-Tang) (13), Daisaikoto (Da-Chai-Hu-Tang) (14), Saireito (Chai-Ling-Tang) (15), Saikokeishito (Chai-Hu-Gui-Zhi-Tang) (16), and Saikokaryukotsuboreito (Chai-Hu-Jia-Long-Gu-Mu-Li-Tang) (17). The medicinal effects of these medicines improve gastrointestinal, liver and breathing responses, targets immune function, and relieves inflammation (18).…”

A review of complementary therapies for chemotherapy induced gastrointestinal mucositis

“…Administration of saireito significantly suppressed the activation of caspase-3 and reduced 5-FU-increased apoptotic cells, with an inhibition rate of 67.8% (60). Furthermore, it significantly attenuated the up-regulation of both TNF-α and IL-1β mRNA induced by 5-FU.…”

“…Furthermore, it significantly attenuated the up-regulation of both TNF-α and IL-1β mRNA induced by 5-FU. The inhibition rate was 72.5 and 77.6% for TNF-α and IL-1β, respectively (60). Iberogast, a mixture of extracts from bitter candytuft (Iberis amara), angelica root (Angelicae radix), milk thistle fruit (Silybi mariani fructus), celandine herb (Chelidonii herba), caraway fruit (Carvi fructus), liquorice root (Liquiritiae radix), peppermint herb (Menthae piperitae folium), balm leaf (Melissae folium) and chamomile flower (Matricariae flos) partially improved the histopathological features of 5-FU induced GIM in rats (61,62).…”

“…Saireito, a traditional Japanese herbal medicine and a combined formulation of two herbal medicines (shosaikoto and goreisan) reduced 5-FU-induced GIM through reduction of apoptosis in the intestinal crypt via suppression of the up-regulation of inflammatory cytokines (60). Administration of saireito significantly suppressed the activation of caspase-3 and reduced 5-FU-increased apoptotic cells, with an inhibition rate of 67.8% (60).…”